Development and Characterization of Transdermal patches of Tramadol Hydrochloride: An Approach to Pain Management

Pooja Dhama*, Sachin Kumar, Manoj Kumar Sagar

NKBR College of Pharmacy and Research Centre, Meerut, U.P. – 245206.

*Corresponding Author E-mail: nkbrcolleges@gmail.com

ABSTRACT:

Transdermal drug delivery leads direct access to the systemic circulation through the skin which bypass drug from the hepatic first pass metabolism leading to increase bioavailability. Because Tramadol hydrochloride has low bioavailability, it was selected as a model drug. The present study was aimed to develop and characterize transdermal patches of Tramadol hydrochloride by solvent casting method. Two polymers Ethyl cellulose (EC) and Poly vinyl pyrrrolidine (PVP) in different combination or alone were used to form matrix system. Dibutylpthlate and Glycerine were incorporated as plasticizers. All the patches were characterized for parameters like Thickness, Weight variation, Drug content uniformity, Tensile strength, % elongation, folding endurance, moister content, In-vitro drug permeation study etc. Amongst all formulations, formulation F6 had more desirable characteristic & shows 82.82% drug permeation in 10 hr. Release kinetic can be described by Higuchi model with anomalous diffusion as a release mechanism. The Transdermal patch formulated from Ethyl Cellulose (EC) and PVP showed satisfactory physicochemical properties. So, it can be concluded that such a matrix type patches of Ethyl Cellulose (EC) and PVP could be a good carrier in transdermal delivery of Tramadol HCl. FTIR studies showed there were no incompatibilities between drug and other excipients.

KEYWORDS: Transdermal patch, Tramadol hydrochloride, PVP, Folding endurance, In vitro permeation.

INTRODUCTION:

Today, the most common form of drug administration is oral. This has obvious advantages in terms of ease of administration, but it has low bioavailability due to hepatic metabolism (first pass) and tends to increase rapidly in the blood. This leads to the need for high and/ or repeated doses, which can be costly and inconvenient.

To overcome these difficulties, a new drug delivery system is needed. By more precise identification (i.e., specific location), temporal placement within the body, this will improve the therapeutic efficacy and safety of the medication, thereby reducing the number and number of doses¹.

In the current scenario of new drug dosage forms, transdermal drug delivery system (TDDS) has established itself as an integral part of the new drug delivery system. Transdermal patches are polymeric compositions that are applied to the skin to release drugs through the skin at a predetermined rate for systemic effects. Although transdermal dosage forms are expensive alternatives to traditional preparations, they have become popular due to their unique advantages².

Controlled absorption, more uniform plasma levels, improved bioavailability, reduced side effects, painless and simple application and flexibility of terminating drug administration by simply removing the patch from the skin are some of the potential advantages of transdermal drug delivery. Development of controlled release transdermal dosage form is a complex process involving extensive efforts³.

Transdermal drug delivery can closely mimic the slow intravenous infusion, without its potential hazards and also offer another most important advantage in allowing the patient to terminate the drug therapy by simply removing the patch at any desired time if toxicity develops. Drugs like estrogens, testosterone, and nitroglycerine when administered orally will be inactivated by gastrointestinal enzymes or environmental difference. Such drugs can now be delivered directly into systemic circulation by a noninvasive transdermal route. On the contrary, transdermal drug delivery mode is not suitable for all drugs, which may be the reason for the fact that only few drugs have been successfully designed and commercialized by different companies. The skin acts as a formidable barrier to the penetration of drugs and other chemicals; it does have certain advantages which make it an alternative route for systemic delivery of drugs⁴. Transdermal drug delivery system involves the passage of substances from the skin surface through the skin layers, into the systemic circulation. The skin has been commonly used as a site for topical administration of drugs, when the skin serves as a port for administration of systemically active drugs⁵. The drug applied topically is distributed following absorption, first into the systemic circulation and then transported to the target tissue, which can be relatively remote from the site of drug application to achieve its therapeutic action. Some of the potential benefits of transdermal drug delivery systems include:

· Avoid first pass metabolism.

· Eliminates irritation of the gastrointestinal tract.

· Less dosing frequency.

· Rapid and long-lasting termination of the drug action.

Tramadol Hydrochloride is a central acting analgesic. Tramadol Hydrochloride acts as a μ-opioid receptor agonist, serotonin releasing agent, norepinephrine reuptake inhibitor, NMDA receptor antagonist, 5-HT_{HYPERLINK
"http://en.wikipedia.org/wiki/5-HT2C_receptor"2C} receptor antagonist, (α7)_{HYPERLINK
"http://en.wikipedia.org/wiki/Alpha-7_nicotinic_receptor"5} nicotinic acetylcholine receptor antagonist, TRPV1 receptor agonist.

Tramadol Hydrochloride a half-life of approximately 6 hours. Frequent doses are therefore necessary. Easily soluble in water, so retarding formulations should be chosen carefully. The purpose of this research is to establish a new, simple, integrated, easy-to-use, inexpensive and aesthetically acceptable drug delivery system for drugs to overcome the traditional "patch" of tramadol. Tramadol is a powerful and atypical synthetic pain reliever that works through two main mechanisms of action (opioids and non-opioids)⁶. The analgesic effect of Tramadol Hydrochloride is not fully understood, but it is believed to work by modulating serotonin and norepinephrine, as well as the relatively weak opioid agonist receptors. The contribution of non-opioid activity is evident from the fact that the effects of Tramadol Hydrochloride analgesics are not completely antagonised with naloxone μ-opioid receptor antagonists⁷.

After oral administration, Tramadol is rapidly absorbed. The peak analgesic effect reaches its maximum within 1 to 4 hours of maximum administration and lasts only 3 to 6 hours of analgesia.

MATERIALS AND METHODS:

Tramadol HCl was obtained as a gift sample from Mylan pharmaceuticals, polymers like PVP is obtained from Hi-media pharma and Ethyl cellulose is obtained as gift samples from Colorcon. The other excipients like Dibutyl Phthalate, Glycerin, Sodium hydroxide and Potassium dihydrogen Orthophosphate are purchased from S.D Fine Chemicals. All the chemicals used were of analytical grade.

Experimental work:

The matrix-type transdermal patches containing tramadol HCL were prepared using different ratios of Ethyl cellulose and PVP. The polymers in different ratios were dissolved in the respective solvents. The resulting homogenous solution was set aside for about 6hrs allowing the polymers to swell after ultra sonication which aids to remove the air bubbles. Then the drug was added slowly in the polymeric solution and stirred on the shaker to obtain a uniform solution. Di-butyl phthalate and glycerin were used as plasticizers. Then the solution was casted in the castor oil applied (1 to 2 drops) to Petri dishes having diameter of 10 and 5 and dried at the room temperature⁸.

Table 1 : Formulation of Tramadol HCl transdermal patches

Formulation	Polymeric Blend	Ration (mg)	Plasticizer (0.30%)	Permeation enhancer	Solvent System
F1	EC:PVP	1:1	DibuthylPthalate	PEG-200	Methanol
F2	EC:PVP	2:1	DibuthylPthalate	PEG-200	Methanol
F3	EC:PVP	4:1	DibuthylPthalate	PEG-200	Methanol
F4	EC:PVP	6:1	DibuthylPthalate	PEG-200	Methanol
F5	EC:PVP	8:1	DibuthylPthalate	PEG-200	Methanol
F6	EC:PVP	10:1	DibuthylPthalate	PEG-200	Methanol

Evaluation of Transdermal Patches:

All the prepared formulations were subjected for preformulation studies like determining the solubility, melting point and drug excipients compatibility studies. Weight variation is studied by individually weighing randomly selected patches and calculating the average weight⁹. The individual weight should not deviate significantly from the average weight.

Physical appearance:

The prepared transdermal patches were physically checked for color, clarity and surface texture

Thickness uniformity:

Use an electronic caliper to measure the thickness of the patch, at least 0.01mm. Measure the thickness in three different places on the film and get an average.

Uniformity of weight:

Cut 1 x 1cm2 patches, take the weight of each patch, and then calculate the average weight of the patch.

Folding endurance:

Measure the folding endurance of the manually prepared patch. Cut the patch (2 x 2cm 2) and fold it over and over in the same position until it breaks. The number of times the film can be folded in the same position without breaking indicates the value of the folding resistance¹⁰.

Percentage moisture content:

The patches were weighed separately and stored in a desiccator containing calcium chloride. If the weight of each patch did not change, the final weight was observed. The moisture percentage is calculated as the difference between the initial weight and the final weight in relation to the final weight¹¹.

Percentage moisture uptake:

The patches were weighed accurately and placed in a desiccator where a humidity condition of 80-90% RH was maintained by using saturated solution of potassium chloride. The patches were kept until uniform weight is obtained, then taken out and weighed. The percentage of moisture uptake was calculated as the difference between final and initial weight with respect to initial weight¹².

Water vapor transmission (WVT) rate:

In this study, vials of equal diameter were used as the transmission cell. The cells are washed thoroughly and dried in an oven. Place approximately 1g of fused calcium chloride in the tank and fix the tip of the polymer 1 cm 2 above the edge with an adhesive. Weigh the sample cell carefully and record the initial weight, then store it in a closed dryer containing a saturated solution of potassium chloride to maintain a relative humidity of 80-90%. Cells were removed and weighed after 24 hours. Use the formula to calculate the transport volume and the transport speed of the water vapor through the weight difference¹³.

The transmission speed of water vapor is generally expressed in grams/hour/cm² of humidity obtained.

Drug content uniformity: The patches were tested for the content uniformity. Cut the patch to a size of 1 square centimeter and place it in a 100 ml volumetric flask. Mix the contents with a 24-hour magnetic bead to dissolve the patch. Then it was diluted with phosphate buffer (pH 7.4). Measure the absorption of the solution with the empty solution corresponding to 209 nm using a UV-visible spectrophotometer. The experiment was repeated more than three times to verify the results¹⁴.

In vitro permeation studies:

Prepare a patch in an area of 1 cm2, place it on a commercial semi-insulated film (accessible for regenerated cellulose in low molecular weight material) and connect it to the diffusion cell so that the cell surface releases the drug in soluble phosphate buffer solution of pH 7.4 at 37±10C. Remove aliquots (1ml) at predetermined time intervals and replace phosphate buffer with a section equal to pH 7.4. An ultraviolet spectrometer was used to analyze the drug content of a 271nm sample^15-16.

Drug release kinetics:

The in vitro permeation data of various formulations was analyzed by fitting the permeation data into various kinetic models to explain permeation profile in case of tramadol hydrochloride transdermal patch, it was observed that all the different formulation of transdermal patch follow zero order kinetics. The n value from drug release experiment for all formulation ranged from 0.605 to 0.660 indicated anomalous non-fickian type diffusion i.e the drug was released by initial swelling of polymer matrix and followed anomalous transport¹⁷.

RESULTS¹⁸:

Melting point:

The melting points were found to be in the range of 180 to 181°C. The reported melting point is 180° to 181.5°C.

Solubility studies:

Solubility studies were carried out in normal distilled water and phosphate buffer.

Table 2: Solubility analysis

Solubility medium	Time duration	Solubility (μg/ml)
Water	24 hour	1.785
Buffer ph 6.8	24 hour	2.014

Figure 1: UV spectrum of Tramadol HCL

Figure 2: Calibration curve of Tramadol hydrochloride

Table 3: Physicochemical evaluation data of Tramadol HCl Transdermal patches

BATCH CODES	F1	F2	F3	F4	F5	F6
Physical Apperearance	++	++	++	++	++	++
Weight variation (mg)	2122.2± 2.4	2623.2± 2.2	3230± 2.2	781.6± 1.3	975.4± 0.8	1012.4± 1.5
Thickness (mm)	0.32 ± 0.01	0.43± 0.08	0.46± 0.09	0.58± 0.06	0.63± 0.06	0.54± 0.01
Drug content (%)	90.3 ±0.018	92.36±0.017	86.65±0.03	93.79±0.015	84.11±0.021	88.77±0.014
Folding endurance	>100	>100	>100	>100	>100	>100
WVT (gcm/cm2.24h)	5.91±0.059	5.57±0.049	5.19±0.035	4.90±0.05	5.99±0.038	6.25±0.029
%Moisture content	1.58 ±0.154	1.42±0.08	1.36±0.05	1.02±0.024	1.09±0.088	1.12±0.02
% Moisture uptake	4.5±0.089	4.9±0.028	4.8±0.094	2.8±0.124	2.4 ±0.056	3.4 ±0.03

In vitro studies:

Table 4: Cumulative % drug permeated versus time across dialysis membrane for formulation F1-F6

Time	F1	F2	F3	F4	F5	F6
30	17.33±0.11361	14.33±0.06557	12.37±0.04726	14.33±0.06557	9.48±0.03606	8.25±0.04509
60	22.37±0.05033	19.28±0.03606	17.41±0.04028	14.28±0.03606	13.45±0.06028	12.19±0.04000
120	31.87±0.03512	24.08±0.04041	24.68±0.04163	24.08±0.04041	18.42±0.06503	17.46±0.05508
180	35.88±0.05023	29.42±0.06506	28.33±0.04509	29.42±0.06506	23.81±0.04509	21.17±0.04583
240	44.83±0.09165	36.37±0.099609	35.13±0.05033	36.37±0.099609	29.97±0.04000	24.42±0.03606
300	51.08±0.02517	42.39±0.04041	41.37±0.04583	42.39±0.04041	37.31±0.05000	29.51±0.03055
360	57.24±0.06110	50.66±0.05568	47.44±0.03501	50.66±0.05568	42.54±0.04583	33.58±0.07024
420	60.74±0.07024	59.13±0.04041	56.19±0.03606	59.13±0.04041	50.07±0.04102	37.58±0.06110
480	69.91±0.03512	68.07±0.02517	65.96±0.04726	68.07±0.02517	56.45±0.05508	43.19±0.040210
540	75.75±0.09165	76.08±0.03055	71.75±0.04509	76.08±0.03055	62.346±0.05606	47.89±0.04509
600	80.76±0.08083		77.69±0.05686	82.82±0.07024	68.42±0.05292	55.37±0.06028

Figure 4:Plot of cumulative % permeated versus time across dialysis membrane for formulation F1-F6

SUMMARY AND CONCLUSION:

The purpose of this research is to establish a new, simple, integrated, easy-to-use, inexpensive and aesthetically acceptable drug delivery system for drugs to overcome the traditional "patch" of tramadol. It is a powerful pain reliever that works through two main mechanisms of action (opioids and non-opioids). After oral administration, It is rapidly absorbed. The peak analgesic effect reaches its maximum within 1 to 4 hours of maximum administration and lasts only 3 to 6 hours of analgesia. In the present study ,the transdemal patches of Tramadol Hydrochloride were prepared by solvent casting using glass mould of known diameter .The patch of tramadol hydrochloride were formed using two polymer ethyl cellulose (EC) ,Polyvinyl pyrrrolidine (PVP) in different combination or alone. Incorporation of dibutylpthlate and glycerine worked as plasticizer (30% w/w and 5% W/W) respectively of dry polymer. The compositon of various formulation shown in table 1.

The preformulation studies were examined and had comparability with official standerd (I.P. 1996). The wavelength range determined utilizing U.V. spectrophotometer was seen as 271 nm¹⁹. EC, PVP, Methanol and Glycerin were utilized in the plan of patches. Six batches of patches were made utilizing different concentration of EC and PVP. Assessment of each bunch was performed and batch F4 was optimed best, since it had closeness with standard properties of transdermal patches. In-vitro permeation study²⁰ gives data that transdermal patches can release 82.82 % of medication.

Transdermal patches of Tramadol Hydrochloride were effectively prepared. The prepared transdermal patches showed great assessment property. The transdermal patches would be potential dosage form for drug delivery for different purpose.

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Received on 02.08.2020 Modified on 25.02.2021

Research J. Pharm. and Tech 2022; 15(1):1-5.

DOI: 10.52711/0974-360X.2022.00001